β-lactamase inhibitor

Abstract

An object is to provide a compound having β-lactamase inhibitory activity. The object is achieved by a compound represented by formula (1), typified by a compound in which specific positions of a 5-membered ring having planarity are replaced by sulfamoyl and carboxy groups.

The invention claimed is: 
     
       1. A β-lactamase inhibitor comprising a compound represented by formula (1) or a salt, hydrate, or solvate thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents —C(—R A )—; 
         R 2  represents —N(—R B ) n —, —O—, or —C(—R A )—; 
         R 3  represents —C(—R A )— when R 2  is —N(—R B ) n — or —O—, or represents —S— when R 2  is —C(—R A )—; 
         each R A  is the same or different and represents a hydrogen atom, a halogen atom, or a hydrocarbon group optionally substituted with one or more amino groups; 
         R B  represents a hydrogen atom, a halogen atom, an optionally substituted amino group, or a hydrocarbon group optionally substituted with one or more amino groups; 
         n represents 0 or 1; 
         R 6  represents a hydrogen atom or a hydrocarbon group; 
         R 7  and R 8  are the same or different and each represents a hydrogen atom or a hydrocarbon group, or R 7  and R 8  are bonded to each other to form a ring with the adjacent nitrogen atom; and 
         a bond represented by a double line composed of a solid line and a dotted line is a single bond or a double bond. 
       
     
     
       2. The inhibitor according to  claim 1 , wherein the β-lactamase is a class B β-lactamase. 
     
     
       3. The inhibitor according to  claim 1 , wherein the β-lactamase is a class B1 β-lactamase. 
     
     
       4. An enhancer of an antimicrobial effect of a β-lactam antimicrobial compound, the enhancer comprising a compound represented by formula (1) or a salt, hydrate, or solvate thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents —C(—R A )—; 
         R 2  represents —N(—R B ) n —, —O—, or —C(—R A )—; 
         R 3  represents —C(—R A )— when R 2  is —N(—R B ) n — or —O—, or represents —S— when R 2  is —C(—R A )—; 
         each R A  is the same or different and represents a hydrogen atom, a halogen atom, or a hydrocarbon group optionally substituted with one or more amino groups; 
         R B  represents a hydrogen atom, a halogen atom, an optionally substituted amino group, or a hydrocarbon group optionally substituted with one or more amino groups; 
         n represents 0 or 1; 
         R 6  represents a hydrogen atom or a hydrocarbon group; 
         R 7  and R 8  are the same or different and each represents a hydrogen atom or a hydrocarbon group, or R 7  and R 8  are bonded to each other to form a ring with the adjacent nitrogen atom; and 
         a bond represented by a double line composed of a solid line and a dotted line is a single bond or a double bond. 
       
     
     
       5. An antimicrobial agent comprising a compound represented by formula (1) or a salt, hydrate, or solvate thereof, and a β-lactam antimicrobial compound, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents —C(—R A )—; 
         R 2  represents —N(—R B ) n —, —O—, or —C(—R A )—; 
         R 3  represents —C(—R A )— when R 2  is —N(—R B ) n — or —O—, or represents —S— when R 2  is —C(—R A )—; 
         each R A  is the same or different and represents a hydrogen atom, a halogen atom, or a hydrocarbon group optionally substituted with one or more amino groups; 
         R B  represents a hydrogen atom, a halogen atom, an optionally substituted amino group, or a hydrocarbon group optionally substituted with one or more amino groups; 
         n represents 0 or 1; 
         R 6  represents a hydrogen atom or a hydrocarbon group; 
         R 7  and R 8  are the same or different and each represents a hydrogen atom or a hydrocarbon group, or R 7  and R 8  are bonded to each other to form a ring with the adjacent nitrogen atom; and 
         a bond represented by a double line composed of a solid line and a dotted line is a single bond or a double bond. 
       
     
     
       6. An antimicrobial agent comprising a β-lactam antimicrobial compound, the antimicrobial agent being for use in administration in combination with a compound represented by formula (1) or a salt, hydrate, or solvate thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents —C(—R A )—; 
         R 2  represents —N(—R B ) n —, —O—, or —C(—R A )—; 
         R 3  represents —C(—R A )— when R 2  is —N(—R B ) n — or —O—, or represents —S— when R 2  is —C(—R A )—; 
         each R A  is the same or different and represents a hydrogen atom, a halogen atom, or a hydrocarbon group optionally substituted with one or more amino groups; 
         R B  represents a hydrogen atom, a halogen atom, an optionally substituted amino group, or a hydrocarbon group optionally substituted with one or more amino groups; 
         n represents 0 or 1; 
         R 6  represents a hydrogen atom or a hydrocarbon group; 
         R 7  and R 8  are the same or different and each represents a hydrogen atom or a hydrocarbon group, or R 7  and R 8  are bonded to each other to form a ring with the adjacent nitrogen atom; and 
         a bond represented by a double line composed of a solid line and a dotted line is a single bond or a double bond. 
       
     
     
       7. A compound represented by formula (1A) or a salt, hydrate, or solvate thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 2  represents —N(—R B )— or —O—; 
         each R A  is the same or different and represents a hydrogen atom, a linear or branched alkyl group optionally substituted with one or more amino groups (with the proviso that when R 2  is —N(—R B )—, the alkyl group has 1 to 5 carbon atoms, and when R 2  is —O—, the alkyl group has 2 to 5 carbon atoms), a C 3-7  cyclic alkyl group optionally substituted with one or more amino groups, or a phenyl group optionally substituted with one or more amino groups; 
         R B  represents a hydrogen atom, an amino group optionally substituted with one or more linear or branched alkyl groups, or an alkyl group optionally substituted with one or more amino groups; 
         R 6  represents a hydrogen atom; and 
         R 7  and R 8  are the same or different and each represents a hydrogen atom or an alkyl group (with the proviso that the case in which both R 7  and R 8  are alkyl groups is excluded), or R 7  and R 8  are bonded to each other to form a ring with the adjacent nitrogen atom. 
       
     
     
       8. The compound or a salt, hydrate, or solvate thereof according to  claim 7 , wherein the alkyl group represented by R B  is a C 1-4  linear alkyl group. 
     
     
       9. A medicament comprising the compound or a salt, hydrate, or solvate thereof according to  claim 7 . 
     
     
       10. A reagent comprising the compound or a salt, hydrate, or solvate thereof according to  claim 7 . 
     
     
       11. The inhibitor according to  claim 2 , wherein the β-lactamase is a class B1 β-lactamase. 
     
     
       12. A medicament comprising the compound or a salt, hydrate, or solvate thereof according to  claim 8 . 
     
     
       13. A reagent comprising the compound or a salt, hydrate, or solvate thereof according to  claim 8 .